Glucagon‐like peptide‐1, corticotropin‐releasing hormone, and hypothalamic neuronal histamine interact in the leptin‐signaling pathway to regulate feeding behavior

Diabetes mellitus exerts metabolic stress on cells and it provokes a chronic increase in the long-term activity of the hypothalamus-pituitary-adrenocortical (HPA) axis, perhaps thereby contributing to insulin resistance. GLP-1 receptor (GLP-1R) agonists are pleiotropic hormones that not only affect glycaemic and metabolic control, but they also produce many other effects including activation of the HPA axis. In fact, several of the most relevant effects of GLP-1 might involve, at least in part, the modulation of the HPA axis. Thus, the anorectic activity of GLP-1 could be mediated by increasing CRF at the hypothalamic level, while its lipolytic effects could imply a local increase in glucocorticoids and glucocorticoid receptor (GC-R) expression in adipose tissue. Indeed, the potent activation of the HPA axis by GLP-1R agonists occurs within the range of therapeutic doses and with a short latency. Interestingly, the interactions of GLP-1 with the HPA axis may underlie most of the effects of GLP-1 on food intake control, glycaemic metabolism, adipose tissue biology and the responses to stress. Moreover, such activity has been observed in animal models (mice and rats), as well as in normal humans and in type I or type II diabetic patients. Accordingly, better understanding of how GLP-1R agonists modulate the activity of the HPA axis in diabetic subjects, especially obese individuals, will be crucial to design new and more efficient therapies for these patients.

show abstract

“…In this regard, pre-treatment with Ex(9-39) attenuates the leptin-induced increase in CRF in the hypothalamus (Fig. 2, Gotoh et al 2005).…”

Section: Glp-1 Gcs and The Control Of Food Intakementioning

confidence: 87%

Stressing diabetes? The hidden links between insulinotropic peptides and the HPA axis

Diz-Chaves

Gil‐Lozano

Toba

et al. 2016

Journal of Endocrinology

View full text Add to dashboard Cite

show abstract

“…It is fundamental for appetitive and aversive responses during motivated behavior (24), and blockade of histamine H 1 R in the hypothalamus is believed to be responsible for the weight gain and metabolic dysregulation associated with the clinical use of atypical antipsychotics (25). Several peptides and hormonessuch as leptin, corticotropin-, TSH-releasing hormones, and nefastin-1-are satiety modulators acting, at least in part, through histamine neurons activity (26)(27)(28). So far, there has been no information regarding brain histamine taking part in the anorexic effects of a modulator that, at the dose used in this study, does not easily pass the blood-brain barrier.…”

Section: Discussionmentioning

confidence: 99%

Satiety factor oleoylethanolamide recruits the brain histaminergic system to inhibit food intake

Provensi

Coccurello

Umehara

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

108

View full text Add to dashboard Cite

Key factors driving eating behavior are hunger and satiety, which are controlled by a complex interplay of central neurotransmitter systems and peripheral stimuli. The lipid-derived messenger oleoylethanolamide (OEA) is released by enterocytes in response to fat intake and indirectly signals satiety to hypothalamic nuclei. Brain histamine is released during the appetitive phase to provide a high level of arousal in anticipation of feeding, and mediates satiety. However, despite the possible functional overlap of satiety signals, it is not known whether histamine participates in OEA-induced hypophagia. Using different experimental settings and diets, we report that the anorexiant effect of OEA is significantly attenuated in mice deficient in the histamine-synthesizing enzyme histidine decarboxylase (HDC-KO) or acutely depleted of histamine via interocerebroventricular infusion of the HDC blocker α-fluoromethylhistidine (α-FMH). α-FMH abolished OEA-induced early occurrence of satiety onset while increasing histamine release in the CNS with an H 3 receptor antagonist-increased hypophagia. OEA augmented histamine release in the cortex of fasted mice within a time window compatible to its anorexic effects. OEA also increased c-Fos expression in the oxytocin neurons of the paraventricular nuclei of WT but not HDC-KO mice. The density of c-Fos immunoreactive neurons in other brain regions that receive histaminergic innervation and participate in the expression of feeding behavior was comparable in OEA-treated WT and HDC-KO mice. Our results demonstrate that OEA requires the integrity of the brain histamine system to fully exert its hypophagic effect and that the oxytocin neuron-rich nuclei are the likely hypothalamic area where brain histamine influences the central effects of OEA.histamine receptors | behavioral satiety sequence | BSS | paraventricular hypothalamic nuclei | PVN E ating behavior is regulated by central neurotransmitter systems and peripheral stimuli that interact to change the behavioral state and concur to alter homeostatic aspects of appetite and energy expenditure. The fatty acid amide oleoylethanolamide (OEA) is released by the small intestine in a stimulus-dependent manner and suppresses food intake by activating peroxisome proliferator-activated receptor-α (PPAR-α) (1). Systemic administration of OEA induces c-Fos mRNA expression through the vagus nerve to the nucleus of the solitary tract (NST), supraoptic nuclei (SON), and paraventricular hypothalamic nuclei (PVN) and increases the expression of oxytocin (2, 3), which is involved in the central coordination of homeostatic signals and feeding behavior (4). However, it is not known whether OEA recruits other neurotransmitter systems in the brain to reduce food intake. Histaminergic neurons are clustered in the hypothalamic tuberomammillary nuclei (TMN). They send projections organized in functionally distinct circuits impinging on different brain regions (5), and their firing frequency changes according to the behavioral state (6). Brain histamin...

show abstract

“…Chronic sucrose consumption results in leptin resistance (19,51). Given the interaction between central leptin and GLP-1 action (16,46,48), it is possible that sucrose feeding impairs the anorectic effects of GLP-1 indirectly via modulation of leptin action. Collectively, these findings implicate central AMPK as a critical signaling molecule in the anorectic effect following central GLP-1R activation.…”

Section: E683mentioning

confidence: 99%

Central glucagon-like peptide 1 receptor-induced anorexia requires glucose metabolism-mediated suppression of AMPK and is impaired by central fructose

Burmeister

Ayala

Drucker

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

View full text Add to dashboard Cite

Burmeister MA, Ayala J, Drucker DJ, Ayala JE. Central glucagon-like peptide 1 receptor-induced anorexia requires glucose metabolism-mediated suppression of AMPK and is impaired by central fructose. Am J Physiol Endocrinol Metab 304: E677-E685, 2013. First published January 22, 2013 doi:10.1152/ajpendo.00446.2012.-Glucagon-like peptide-1 (GLP-1) suppresses food intake via activation of a central (i.e., brain) GLP-1 receptor (GLP-1R). Central AMP-activated protein kinase (AMPK) is a nutrient-sensitive regulator of food intake that is inhibited by anorectic signals. The anorectic effect elicited by hindbrain GLP-1R activation is attenuated by the AMPK stimulator AICAR. This suggests that central GLP-1R activation suppresses food intake via inhibition of central AMPK. The present studies examined the mechanism(s) by which central GLP-1R activation inhibits AMPK. Supporting previous findings, AICAR attenuated the anorectic effect elicited by intracerebroventricular (icv) administration of the GLP-1R agonist exendin-4 (Ex-4). We demonstrate that Ex-4 stimulates glycolysis and suppresses AMPK phosphorylation in a glucose-dependent manner in hypothalamic GT1-7 cells. This suggests that inhibition of AMPK and food intake by Ex-4 requires central glucose metabolism. Supporting this, the glycolytic inhibitor 2-deoxyglucose (2-DG) attenuated the anorectic effect of Ex-4. However, icv glucose did not enhance the suppression of food intake by Ex-4. AICAR had no effect on Ex-4-mediated reduction in locomotor activity. We also tested whether other carbohydrates affect the anorectic response to Ex-4. Intracerebroventricular pretreatment with the sucrose metabolite fructose, an AMPK activator, attenuated the anorectic effect of Ex-4. This potentially explains the increased food intake observed in sucrose-fed mice. In summary, we propose a model whereby activation of the central GLP-1R reduces food intake via glucose metabolism-dependent inhibition of central AMPK. We also suggest that fructose stimulates food intake by impairing central GLP-1R action. This has significant implications given the correlation between sugar consumption and obesity.glucagon-like peptide 1; adenosine 5=-monophosphate-activated kinase; food intake; glucose; fructose HEALTH RISKS ASSOCIATED WITH OBESITY, including cardiovascular disease, diabetes, and cancer, highlight the importance of understanding mechanisms that control food intake and how they become impaired. Food intake is regulated by neural and hormonal signals that match caloric intake with the chronic and acute energy needs of the organism. Although significant attention has been given to understanding mechanisms associated with adiposity signals such as leptin and insulin, less is known about acute satiety mechanisms regulated by signals such as glucagon-like peptide-1 (GLP-1).GLP-1 is secreted from intestinal L cells in response to nutrient intake and was identified for its ability to stimulate insulin secretion via activation of a pancreatic ␤-cell GLP-1 receptor (GLP-1R) (3). GLP-1 also r...

show abstract

Glucagon‐like peptide‐1, corticotropin‐releasing hormone, and hypothalamic neuronal histamine interact in the leptin‐signaling pathway to regulate feeding behavior

Cited by 53 publications

References 28 publications

Stressing diabetes? The hidden links between insulinotropic peptides and the HPA axis

Stressing diabetes? The hidden links between insulinotropic peptides and the HPA axis

Satiety factor oleoylethanolamide recruits the brain histaminergic system to inhibit food intake

Central glucagon-like peptide 1 receptor-induced anorexia requires glucose metabolism-mediated suppression of AMPK and is impaired by central fructose

Contact Info

Product

Resources

About